Integrated long-read transcriptomics of aging mouse pituitary reveals Pou1f1 vulnerability and novel isoform remodeling

Although age-related changes in pituitary hormone levels, including growth hormone (GH), have been documented, the molecular mechanisms underlying pituitary aging and its effects on full-length transcript isoforms remain poorly understood. Here, we performed full-length long-read transcriptomic sequencing (Iso-Seq) of anterior pituitary glands from young and old male mice to comprehensively characterize aging-associated changes in gene expression, isoform usage, and alternative splicing.

Integration of differential expression, isoform-switch, and novel isoform analyses identified Pou1f1 as the most significantly downregulated gene in aged pituitaries (log₂FC = −2.02, Padj = 1.02 × 10⁻³⁰), accompanied by reduced expression of genes involved in neurosecretory function, including Syn1, Syt7, Dvl3, and Cacna2d2. Notably, aging was associated with a directional accumulation of novel isoforms, with more isoforms enriched in old than young pituitaries (100 vs. 55; binomial P = 0.0004), together with a global shift toward shorter 3′ UTRs (9.6% reduction in length).